Litoamentenes A-K, eleven undescribed cembranoids with cytotoxicity from the South China Sea soft coral Litophyton amentaceum.

Eleven undescribed cembrane-type diterpenoids, named litoamentenes A-K (1-11), were isolated from the soft coral Litophyton amentaceum collected from the South China Sea. Their structures were elucidated by extensive analysis of spectroscopic data, comparison with the literature data, single crystal X-ray diffraction, quantum chemical calculations and TDDFT-ECD calculations. This is the first systematic investigation of L. amentaceum. In particular, compounds 1-3 are cembrane-type norditerpenoids that lack isopropyl side chains. Compound 6 is a cembrane-type norditerpenoid without a methyl group at C-4, the first natural product identified with this carbon skeleton. Compounds 6, 9 and 10 showed modest cytotoxicity against several human cancer cell lines with IC50 values ranging from 3.99 to 14.56 µM.

Circ-0075305 hinders gastric cancer stem cells by indirectly disrupting TCF4-ß-catenin complex and downregulation of SOX9.

CircRNAs are covalently closed, single-stranded RNA that form continuous loops and play a crucial role in the initiation and progression of tumors. Cancer stem cells (CSCs) are indispensable for cancer development; however, the regulation of cancer stem cell-like properties in gastric cancer (GC) and its specific mechanism remain poorly understood. We elucidate the specific role of Circ-0075305 in GC stem cell properties. Circ-0075305 associated with chemotherapy resistance was identified by sequencing GC cells. Subsequent confirmation in both GC tissues and cell lines revealed that patients with high expression of Circ-0075305 had significantly better overall survival (OS) rates than those with low expression, particularly when treated with postoperative adjuvant chemotherapy for GC. In vitro and in vivo experiments confirmed that overexpression of Circ-0075305 can effectively reduce stem cell-like properties and enhance the sensitivity of GC cells to Oxaliplatin compared with the control group. Circ-0075305 promotes RPRD1A expression by acting as a sponge for corresponding miRNAs. The addition of LF3 (a ß-catenin/TCF4 interaction antagonist) confirmed that RPRD1A inhibited the formation of the TCF4-ß-catenin transcription complex through competitive to ß-catenin and suppressed the transcriptional activity of stem cell markers such as SOX9 via the Wnt/ß-catenin signaling pathway. This leads to the downregulation of stem cell-like property-related markers in GC. This study revealed the underlying mechanisms that regulate Circ-0075305 in GCSCs and suggests that its role in reducing ß-catenin signaling may serve as a potential therapeutic candidate.

Lemneolemnanes A-D, Four Uncommon Sesquiterpenoids from the Soft Coral Lemnalia sp.

Four undescribed sesquiterpenoids, lemneolemnanes A-D (1-4), have been isolated from the marine soft coral Lemnalia sp. The absolute configurations of the stereogenic carbons of 1-4 were determined by single-crystal X-ray crystallographic analysis. Compounds 1 and 2 are epimers at C-3 and have an unusual skeleton with a formyl group on C-6. Compound 3 possesses an uncommonly rearranged carbon skeleton, while 4 has a 6/5/5 tricyclic system. Compound 1 showed significant anti-Alzheimer's disease (AD) activity in a humanized Caenorhabditis elegans AD pathological model.

Palladium/Norbornene Cooperative Catalysis Bifunctionalization: Acylation/Cyanation of Aryl Iodides by Cleaving C-CN Bond of Aryl Acyl Nitrile.

A palladium/norbornene catalyzed two-component coupling process involving acylation/cyanation of aryl iodides is reported. In this work, aryl acyl nitrile compounds are cleverly selected to provide both nitrile and acyl sources by palladium-catalyzed cleavage of the C-CN bond as both an electrophilic reagent and a termination reagent. This is the first example of C-CN bond cleavage bifunctionalization of aryl iodides. After a series of important NBE derivatives are screened, the products resulting from the bifunctionalization of aryl iodides are smoothly obtained. This strategy has a wide range of substrates and good functional group compatibility. Moreover, this synthetic protocol demonstrated a good application for the synthesis of diverse O,N,C-substituted isoindolinones.

Recent advances in lipid nanovesicles for targeted treatment of spinal cord injury.

The effective regeneration and functional restoration of damaged spinal cord tissue have been a long-standing concern in regenerative medicine. Treatment of spinal cord injury (SCI) is challenging due to the obstruction of the blood-spinal cord barrier (BSCB), the lack of targeting of drugs, and the complex pathophysiology of injury sites. Lipid nanovesicles, including cell-derived nanovesicles and synthetic lipid nanovesicles, are highly biocompatible and can penetrate BSCB, and are therefore effective delivery systems for targeted treatment of SCI. We summarize the progress of lipid nanovesicles for the targeted treatment of SCI, discuss their advantages and challenges, and provide a perspective on the application of lipid nanovesicles for SCI treatment. Although most of the lipid nanovesicle-based therapy of SCI is still in preclinical studies, this low immunogenicity, low toxicity, and highly engineerable nanovesicles will hold great promise for future spinal cord injury treatments.

The application of radiomics in esophageal cancer: Predicting the response after neoadjuvant therapy.

Esophageal cancer (EC) is one of the fatal malignant neoplasms worldwide. Neoadjuvant therapy (NAT) combined with surgery has become the standard treatment for locally advanced EC. However, the treatment efficacy for patients with EC who received NAT varies from patient to patient. Currently, the evaluation of efficacy after NAT for EC lacks accurate and uniform criteria. Radiomics is a multi-parameter quantitative approach for developing medical imaging in the era of precision medicine and has provided a novel view of medical images. As a non-invasive image analysis method, radiomics is an inevitable trend in NAT efficacy prediction and prognosis classification of EC by analyzing the high-throughput imaging features of lesions extracted from medical images. In this literature review, we discuss the definition and workflow of radiomics, the advances in efficacy prediction after NAT, and the current application of radiomics for predicting efficacy after NAT.

Prediction of high-grade patterns of stage IA lung invasive adenocarcinoma based on high-resolution CT features: a bicentric study.

OBJECTIVES: This study aims to predict the high-grade pattern (HGP) of stage IA lung invasive adenocarcinoma (IAC) based on the high-resolution CT (HRCT) features. METHODS: The clinical, pathological, and HRCT imaging data of 457 patients (from bicentric) with pathologically confirmed stage IA IAC (459 lesions in total) were retrospectively analyzed. The 459 lesions were classified into high-grade pattern (HGP) (n = 101) and non-high-grade pattern (n-HGP) (n = 358) groups depending on the presence of HGP (micropapillary and solid) in pathological results. The clinical and pathological data contained age, gender, smoking history, tumor stage, pathological type, and presence or absence of tumor spread through air spaces (STAS). CT features consisted of lesion location, size, density, shape, spiculation, lobulation, vacuole, air bronchogram, and pleural indentation. The independent predictors for HGP were screened by univariable and multivariable logistic regression analyses. The clinical, CT, and clinical-CT models were constructed according to the multivariable analysis results. RESULTS: The multivariate analysis suggested the independent predictors of HGP, encompassing tumor size (p = 0.001; OR = 1.090, 95% CI 1.035-1.148), density (p < 0.001; OR = 9.454, 95% CI 4.911-18.199), and lobulation (p = 0.002; OR = 2.722, 95% CI 1.438-5.154). The AUC values of clinical, CT, and clinical-CT models for predicting HGP were 0.641 (95% CI 0.583-0.699) (sensitivity = 69.3%, specificity = 79.2%), 0.851 (95% CI 0.806-0.896) (sensitivity = 79.2%, specificity = 79.6%), and 0.852 (95% CI 0.808-0.896) (sensitivity = 74.3%, specificity = 85.8%). CONCLUSION: The logistic regression model based on HRCT features has a good diagnostic performance for the high-grade pattern of stage IA IAC. KEY POINTS: • The AUC values of clinical, CT, and clinical-CT models for predicting high-grade patterns were 0.641 (95% CI 0.583-0.699), 0.851 (95% CI 0.806-0.896), and 0.852 (95% CI 0.808-0.896). • Tumor size, density, and lobulation were independent predictive markers for high-grade patterns. • The logistic regression model based on HRCT features has a good diagnostic performance for the high-grade patterns of invasive adenocarcinoma.

Two pairs of epimers and three undescribed diterpenoids from Pseudocaryopteris paniculata.

A phytochemical investigation on the petroleum ether partition of the whole plant of Pseudocaryopteris paniculata, yield seven new compounds: one phytanes diterpenoid (2Z,6E,10E) 14-keto-2,6,10-trimethyl pentadeca-2,6,10-trien-1-carboxylic acid (1), five clerodane diterpenoids: paniculatins A-E (2, 3a/3b, 4a/4b), one abietane diterpenoid: ent-uncinatone (5), together with 12 known compounds. Their structures were elucidated on the basis of 1D and 2D Nuclear Magnetic Resonance （NMR_, Infrared Radiation (IR), and mass spectroscopic data. Compound 2, 5, and 11 showed weak selective cytotoxic activity of 11 human cancer cell lines.

A novel web-based dynamic nomogram for recurrent laryngeal nerve lymph node metastasis in esophageal squamous cell carcinoma.

Background: Patients with esophageal squamous cell carcinoma (ESCC) are liable to develop recurrent laryngeal nerve (RLN) lymph node metastasis (LNM). We aimed to assess the predictive value of the long diameter (LD) and short diameter (SD) of RLN lymph node (LN) and construct a web-based dynamic nomogram for RLN LNM prediction. Methods: We reviewed 186 ESCC patients who underwent RLN LN dissection from January 2016 to December 2018 in the Affiliated Hospital of North Sichuan Medical College. Risk factors for left and right RLN LNM were determined by univariate and multivariate analyses. A web-based dynamic nomogram was constructed by using logistic regression. The performance was assessed by the area under the curve (AUC) and Brier score. Models were internally validated by performing five-fold cross-validation. Results: Patients who underwent left and right RLN LN dissection were categorized as left cohort (n = 132) and right cohort (n = 159), with RLN LNM rates of 15.9% (21/132) and 21.4% (34/159), respectively. The AUCs of the LD (SD) of RLN LN were 0.663 (0.688) in the left cohort and 0.696 (0.705) in the right cohort. The multivariate analysis showed that age, the SD of RLN LN, and clinical T stage were significant risk factors for left RLN LNM (all P < 0.05), while tumor location, the SD of RLN LN, and clinical T stage were significant risk factors for right RLN LNM (all P < 0.05). The dynamic nomograms showed reliable performance after five-fold cross-validation [(left (right), mean AUC: 0.814, range: 0.614-0.891 (0.775, range: 0.084-0.126); mean Brier score: 0.103, range: 0.084-0.126 (0.145, range: 0.105-0.206)], available at https://mpthtw.shinyapps.io/leftnomo/ and https://mpthtw.shinyapps.io/rightnomo/. Conclusion: The LD and SD of RLN LN are inadequate to predict RLN LNM accurately, but online dynamic nomograms by combined risk factors show better prediction performance and convenient clinical application.

Cobalt-catalyzed chemoselective dehydrogenation through radical translocation under visible light.

The transformations that allow the direct removal of hydrogen from their corresponding saturated counterparts by the dehydrogenative strategy are a dream reaction that has remained largely underexplored. In this report, a straightforward and robust cobaloxime-catalyzed photochemical dehydrogenation strategy via intramolecular HAT is described for the first time. The reaction proceeds through an intramolecular radical translocation followed by the cobalt assisted dehydrogenation without needing any other external photosensitizers, noble-metals or oxidants. With this approach, a series of valuable unsaturated compounds such as α,ß-unsaturated amides, enamides and allylic and homoallylic sulfonamides were obtained in moderate to excellent yields with good chemo- and regioselectivities, and the synthetic versatility was demonstrated by a range of transformations. And mechanistic studies of the method are discussed.

[Research status and prospects of integration of habitat processing and processing of Chinese medicinal decoction pieces].

The integration of habitat processing and processing of Chinese medicinal decoction pieces(hereinafter referred to as "integration") has changed the traditional processing mode and can ensure the quality of Chinese medicinal decoction pieces from the source. This paper introduced the background of integration from the connotation and denotation of integration, relevant policies and regulations, and variety development. The present situation of integration was analyzed from the existing problems and current research progress, and the development suggestions were proposed. It is considered that although the integration is in line with the development trend of the industry with the advantages of improving the quality and standardizing the management of decoction pieces, there are still some problems, such as the lack of variety selection principles and production technical specifications, imperfect quality control stan-dards in the production process, and inadequate integration of standards and supervision. Therefore, it is suggested to determine the integrated variety selection principles and variety range as soon as possible, establish relevant technical specifications, improve quality control standards in the production process, and strengthen policy guidance and supervision to promote the healthy and orderly development of integration.

Research progress of new isothermal amplification technology in rapid diagnosis of Plasmodium and other parasites / 中国热带医学

@#Abstract: At present, nucleic acid detection technology based on the PCR principle is commonly used to detect malaria parasites, the existing Plasmodium detection methods mainly include microscopy, antigen immunoassay, and nucleic acid detection,but due to the long detection time, high personnel and equipment requirements, and other shortcomings, its popularization, and application at the grassroots level are limited. What challenges previous Plasmodium detection methods are the lack of experienced professionals and advanced equipment at the grassroots as well as the requirement of rapid detection of large samples under extreme conditions. The isothermal amplification technology developed in recent years has potential application prospects due to its simplicity, rapidity, high sensitivity, and high specificity. This article attempts to review the principles, characteristics, and prospects of various isothermal amplification technologies, and on this basis, focuses on the introduction of recombinase polymerase amplification (RPA) and recombinase⁃aided isothermal amplification (RAA) assay technologies and proposes the use of such recombinant enzyme amplification technologies to achieve rapid and accurate diagnosis of common Plasmodium species possibility and imagination.

Diterpenoid glycosides from the flower of Trollius chinensis Bunge and their nitric oxide inhibitory activities.

Trolliusditerpenosides A-Q (1-17), seventeen new labdane-diterpenoid glycosides, were isolated from the dried flowers of Trollius chinensis Bunge, a plant that has been commonly used as both an anti-inflammatory folk medicine and a healthcare tea for its therapeutic and anti-viral and antibacterial properties. Their structures were corroborated via comprehensive spectroscopic analysis, ECD calculations, and single-crystal X-ray diffraction analysis. Furthermore, the inhibitory activities on lipopolysaccharide (LPS)-induced NO production in RAW 264.7 macrophages of all compounds (1-17) were evaluated in vitro. Compounds 3, 6, 7, and 11 displayed significant inhibitory activities against NO production, with IC50 values ranging from 1.6 ± 0.1 to 14.4 ± 0.2 µM. In addition, compounds 3, 6, 7, and 11 all down-regulated the mRNA expression of iNOS, COX-2, and IL-1ß in RAW 264.7 cells mediated by LPS. These findings not only support the chemical context of genus Trollius but also the exploration of new chemical entities with pharmacological significance from this genus.

Lipoprotein(a) is associated with coronary atheroma progression: analysis from a serial coronary computed tomography angiography study.

BACKGROUND: Lipoprotein(a) [Lp(a)] has been closely related to coronary atherosclerosis and might affect perivascular inflammation due to its proinflammatory properties. However, there are limited data about Lp(a) and related perivascular inflammation on coronary atheroma progression. Therefore, this study aimed to investigate the associations between Lp(a) and the perivascular fat attenuation index (FAI) with coronary atheroma progression detected by coronary computed tomography angiography (CCTA). METHODS: Patients who underwent serial CCTA examinations without a history of revascularization and with available data for Lp(a) within one month before or after baseline and follow-up CCTA imaging scans were considered to be included. CCTA quantitative analyses were performed to obtain the total plaque volume (TPV) and the perivascular FAI. Coronary plaque progression (PP) was defined as a ≥ 10% increase in the change of the TPV at the patient level or the presence of new-onset coronary atheroma lesions. The associations between Lp(a) or the perivascular FAI with PP were examined by multivariate logistic regression. RESULTS: A total of 116 patients were ultimately enrolled in the present study with a mean CCTA interscan interval of 30.80 ± 13.50 months. Among the 116 patients (mean age: 53.49 ± 10.21 years, males: 83.6%), 32 patients presented PP during the follow-up interval. Lp(a) levels were significantly higher among PP patients than those among non-PP patients at both baseline [15.80 (9.09-33.60) mg/dLvs. 10.50 (4.75-19.71) mg/dL,P = 0.029] and follow-up [20.60 (10.45-34.55) mg/dLvs. 8.77 (5.00-18.78) mg/dL,P = 0.004]. However, there were no differences in the perivascular FAI between PP group and non-PP group at either baseline or follow-up. Multivariate logistic regression analysis showed that elevated baseline Lp(a) level (OR = 1.031, 95% CI: 1.005-1.058,P = 0.019) was an independent risk factor for PP after adjustment for other conventional variables. CONCLUSIONS: Lp(a) was independently associated with coronary atheroma progression beyond low-density lipoprotein cholesterol and other conventional risk factors. Further studies are warranted to identify the inflammation effect exhibited as the perivascular FAI on coronary atheroma progression.

Increasing rates of long-term nitrogen deposition consistently increased litter decomposition in a semi-arid grassland.

The continuing nitrogen (N) deposition observed worldwide alters ecosystem nutrient cycling and ecosystem functioning. Litter decomposition is a key process contributing to these changes, but the numerous mechanisms for altered decomposition remain poorly identified. We assessed these different mechanisms with a decomposition experiment using litter from four abundant species (Achnatherum sibiricum, Agropyron cristatum, Leymus chinensis and Stipa grandis) and litter mixtures representing treatment-specific community composition in a semi-arid grassland under long-term simulation of six different rates of N deposition. Decomposition increased consistently with increasing rates of N addition in all litter types. Higher soil manganese (Mn) availability, which apparently was a consequence of N addition-induced lower soil pH, was the most important factor for faster decomposition. Soil C : N ratios were lower with N addition that subsequently led to markedly higher bacterial to fungal ratios, which also stimulated litter decomposition. Several factors contributed jointly to higher rates of litter decomposition in response to N deposition. Shifts in plant species composition and litter quality played a minor role compared to N-driven reductions in soil pH and C : N, which increased soil Mn availability and altered microbial community structure. The soil-driven effect on decomposition reported here may have long-lasting impacts on nutrient cycling, soil organic matter dynamics and ecosystem functioning.

Downregulation of T7 RNA polymerase transcription enhances pET-based recombinant protein production in Escherichia coli BL21 (DE3) by suppressing autolysis.

Escherichia coli BL21 (DE3) is an excellent and widely used host for recombinant protein production. Many variant hosts were developed from BL21 (DE3), but improving the expression of specific proteins remains a major challenge in biotechnology. In this study, we found that when BL21 (DE3) overexpressed glucose dehydrogenase (GDH), a significant industrial enzyme, severe cell autolysis was induced. Subsequently, we observed this phenomenon in the expression of 10 other recombinant proteins. This precludes a further increase of the produced enzyme activity by extending the fermentation time, which is not conducive to the reduction of industrial enzyme production costs. Analysis of membrane structure and messenger RNA expression analysis showed that cells could underwent a form of programmed cell death (PCD) during the autolysis period. However, blocking three known PCD pathways in BL21 (DE3) did not completely alleviate autolysis completely. Consequently, we attempted to develop a strong expression host resistant to autolysis by controlling the speed of recombinant protein expression. To find a more suitable protein expression rate, the high- and low-strength promoter lacUV5 and lac were shuffled and recombined to yield the promoter variants lacUV5-1A and lac-1G. The results showed that only one base in lac promoter needs to be changed, and the A at the +1 position was changed to a G, resulting in the improved host BL21 (DE3-lac1G), which resistant to autolysis. As a consequence, the GDH activity at 43 h was greatly increased from 37.5 to 452.0 U/ml. In scale-up fermentation, the new host was able to produce the model enzyme with a high rate of 89.55 U/ml/h at 43 h, compared to only 3 U/ml/h achieved using BL21 (DE3). Importantly, BL21 (DE3-lac1G) also successfully improved the production of 10 other enzymes. The engineered E. coli strain constructed in this study conveniently optimizes recombinant protein overexpression by suppressing cell autolysis, and shows great potential for industrial applications.

From a Designer Drug to the Discovery of Selective Cannabinoid Type 2 Receptor Agonists with Favorable Pharmacokinetic Profiles for the Treatment of Systemic Sclerosis.

Synthetic cannabinoids, as exemplified by SDB-001 (1), bind to both CB1 and CB2 receptors and exert cannabimimetic effects similar to (-)-trans-Δ9-tetrahydrocannabinol, the main psychoactive component present in the cannabis plant. As CB1 receptor ligands were found to have severe adverse psychiatric effects, increased attention was turned to exploiting the potential therapeutic value of the CB2 receptor. In our efforts to discover novel and selective CB2 receptor agonists, 1 was selected as a starting point for hit molecule identification and a class of 1H-pyrazole-3-carboxamide derivatives were thus designed, synthesized, and biologically evaluated. Systematic structure-activity relationship investigations resulted in the identification of the most promising compound 66 as a selective CB2 receptor agonist with favorable pharmacokinetic profiles. Especially, 66 treatment significantly attenuated dermal inflammation and fibrosis in a bleomycin-induced mouse model of systemic sclerosis, supporting that CB2 receptor agonists might serve as potential therapeutics for treating systemic sclerosis.

Gut microbiota and diabetes: From correlation to causality and mechanism.

In this review, we summarize the recent microbiome studies related to diabetes disease and discuss the key findings that show the early emerging potential causal roles for diabetes. On a global scale, diabetes causes a significant negative impact to the health status of human populations. This review covers type 1 diabetes and type 2 diabetes. We examine promising studies which lead to a better understanding of the potential mechanism of microbiota in diabetes diseases. It appears that the human oral and gut microbiota are deeply interdigitated with diabetes. It is that simple. Recent studies of the human microbiome are capturing the attention of scientists and healthcare practitioners worldwide by focusing on the interplay of gut microbiome and diabetes. These studies focus on the role and the potential impact of intestinal microflora in diabetes. We paint a clear picture of how strongly microbes are linked and associated, both positively and negatively, with the fundamental and essential parts of diabetes in humans. The microflora seems to have an endless capacity to impact and transform diabetes. We conclude that there is clear and growing evidence of a close relationship between the microbiota and diabetes and this is worthy of future investments and research efforts.

Probiotics and fructo-oligosaccharide intervention modulate the microbiota-gut brain axis to improve autism spectrum reducing also the hyper-serotonergic state and the dopamine metabolism disorder.

The prevalence of autism spectrum disorders (ASD) is increasing, but its etiology remains elusive and hence an effective treatment is not available. Previous research conducted on animal models suggests that microbiota-gut-brain axis may contribute to ASD pathology and more human research is needed. This study was divided into two stages,.At the discovery stage, we compared the differences in gut microbiota profiles (using 16S rRNA sequencing), fecal SCFAs (using GC-MS) and plasma neurotransmitters (using UHPLC-MS/MS) of 26 children with ASD and 24 normal children. All 26 children with ASD participated in the intervention stage, and we measured the gut microbiota profiles, SCFAs and neurotransmitters before and after probiotics + FOS (n = 16) or placebo supplementation (n = 10). We found that gut microbiota was in a state of dysbiosis and significantly lower levels of Bifidobacteriales and Bifidobacterium longum were observed at the discovery stage in children with ASD. An increase in beneficial bacteria (Bifidobacteriales and B. longum) and suppression of suspected pathogenic bacteria (Clostridium) emerged after probiotics + FOS intervention, with significant reduction in the severity of autism and gastrointestinal symptoms. Compared to children in the control group, significantly lower levels of acetic acid, propionic acid and butyric acid were found, and a hyperserotonergic state (increased serotonin) and dopamine metabolism disorder (decreased homovanillic acid) were observed in children with ASD. Interestingly, the above SCFAs in children with autism significantly elevated after probiotics + FOS intervention and approached those in the control group. In addition, our data demonstrated that decreased serotonin and increased homovanillic acid emerged after probiotics + FOS intervention. However, the above-mentioned changes did not appear in the placebo group for ASD children. Probiotics + FOS intervention can modulate gut microbiota, SCFAs and serotonin in association with improved ASD symptoms, including a hyper-serotonergic state and dopamine metabolism disorder.